Project Abstract Birth defects are a leading cause of infant mortality, morbidity and healthcare costs, yet the etiology of most birth defects remains unknown. Established in 2002, the North Carolina Center for Birth Defects Research and Prevention (NCCBDRP) has been a major contributor to the National Birth Defects Prevention Study (NBDPS) and Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS I). The NCCBDRP is a collaboration between the Department of Epidemiology at the Universityof North Carolina (UNC) Gillings School of Global Public Health in Chapel Hill, and the North Carolina Birth Defects Monitoring Program (NCBDMP) at the North Carolina Division of Public Health in Raleigh. BD-STEPS II will build upon NBDPS' and BD-STEPS I's population-based, multi-center case-control study design to identify causes of birth defects using epidemiologic and genetic research methods, and provide information with strong potential for translation to public health prevention efforts. The NCCBDRP's Specific Aims are to (1) Implement the standardized BD- STEPS II protocol in our well-defined, demographically diverse study region, including: (a) Utilize our enhanced birth defects surveillance system to identify at least 200 eligible cases in the 33 county study area each year; (b) Utilize birth certificates to identify an eligible sample of 100 control infants per year; (c) Conduct clinical case review and classification by clinical geneticist and pediatric cardiologist; (d) Obtain consent from NC participants for supplemental data collection including newborn blood spots and access to health care claims data; and (e) Obtain residual newborn blood spots from the NC State Laboratory; (2) Collect information on early pregnancy exposure to modifiable risk factors via a maternal telephone interview with a specific focus on maternal chronic disease and their treatments, infectious disease in pregnancy, and medications; (3) Link consented NC participants to the Electronic Disease Surveillance System to ascertain information about reportable infections before and during pregnancy; (4) Develop innovative study proposals using NBDPS and BD-STEPS data with maximum potential for public health impact, conduct rigorous analyses, present findings at national meetings, and publish at least 10 papers during the 5-year award period; (5) Conduct a pilot study to validate self-reported prescription medication use by linking case and control mothers with population-level health care claims; (6) Conduct innovative laboratory research to develop methods for using residual newborn blood spots to investigate potential genetic, epigenetic, and environmental risk factors for birth defects; (7) Provide expertise on the application of epidemiologic, genetic/epigenetic, and biostatistical methods to birth defects research; (8) Participate in collaborative research initiatives with other CBDRP and the CDC; and (9) Continue to train the future generation of birth defect researchers. The NC Center is ideally positioned to leverage our demonstrated record of success and participate fully in BD-STEPS II to advance our understanding of the causes of major structural birth defects and prevent cases of birth defects in the future.